Beta-lactamase formulations and uses thereof
The present invention provides, in part, formulations comprising a beta-lactamase. Particularly, modified-release formulations comprising a beta-lactamase are provided which release a substantial amount of the beta-lactamase in the intestines. Therapeutic uses of the beta-lactamase formulations are also provided.
1. A modified-release formulation comprising a beta-lactamase, wherein the formulation comprises at least one modified-release pellet, and wherein each modified-release pellet comprises:
about 10-20% by weight beta-lactamase which comprises an amino acid sequence having at least 98% sequence identity to SEQ ID NO: 1;
about 20-30% by weight sucrose sphere;
about 30-40% by weight binder excipient;
about 15-25% by weight an enteric polymer;
about 1.5-2.5% by weight plasticizer;
about 0.5-1.5% by weight glidant;
about 0.1-1.0% by weight surfactant; and
about 1-2% by weight of buffer salt.
2. The modified-release formulation of claim 1 , wherein each modified-release pellet comprises:
about 16% by weight beta-lactamase;
about 23% by weight sucrose sphere;
about 35% by weight binder excipient;
about 21% by weight an enteric polymer;
about 2% by weight plasticizer;
about 1% by weight glidant;
about 0.5% by weight surfactant; and
about 2% by weight of buffer salt.
3. The modified-release formulation of claim 1 , wherein each modified-release pellet comprises:
about 15.8% by weight beta-lactamase;
about 23.3% by weight sucrose sphere;
about 35% by weight binder excipient;
about 20.8% by weight an enteric polymer;
about 2.1% by weight plasticizer;
about 1% by weight glidant;
about 0.4% by weight surfactant; and
about 1.6% by weight of buffer salt.
4. The modified-release formulation of claim 1 , wherein the beta-lactamase is released in the GI tract.
5. The modified-release formulation of claim 4 , wherein the beta-lactamase is released in the intestines.
6. The modified-release formulation of claim 1 , wherein each modified-release pellet comprises a core particle and a base coat over the core particle, wherein the base coat comprises the beta-lactamase.
7. The modified-release formulation of claim 1 , wherein the formulation comprises a plurality of modified-release pellets.
8. The modified-release formulation of claim 1 , wherein the formulation further comprises a modified-release coating that is stable in gastric fluid.
9. The modified-release formulation of claim 1 , wherein the formulation further comprises a modified-release coating that is pH-dependent.
10. The modified-release formulation of claim 9 , wherein the modified-release coating comprises a poly(methacrylic acid-co-methylmethacrylate) compound.
11. A method of treating or preventing an antibiotic-induced adverse effect in the gastrointestinal tract, a Clostridium difficile infection (CDI) and/or a Clostridium difficile -associated disease, comprising administering the modified-release formulation of claim 1 to a patient in need thereof, wherein the antibiotic is a beta-lactam antibiotic.
12. The method of claim 11 , wherein the antibiotic-induced adverse effect and/or CDI or C. difficile -associated disease is one or more of: antibiotic-associated diarrhea, C. difficile diarrhea (CDD), a Clostridium difficile intestinal inflammatory disease, colitis, pseudomembranous colitis, fever, abdominal pain, dehydration and disturbances in electrolytes.